The proposed supplement application is to cover the increased laboratory rental at the Marine Biological Laboratory, Woods, Hole, Mass. It will be raised twice in 1973. The proposed research has a dual aim, i.e. to elucidate the mode of action of a wide variety of neuroactive agents on nerve membranes, and to clarify the mechanisms underlying membrane ionic conductances by using some of the agents as tools. These two goals complement each other and we will integrate them in an attempt to interpret the molecular Mechanisms of drug action and excitation in nerve membranes. Three major approaches will be used: 1) Electrophysiological methods such as voltage clamp and internal perfusion are extensively used for the study of the mode of action of drugs; 2) Computer controlled voltage clamp and data analyses for the study of the kinetic processes responsible for membrane conductances; and 3) isolation and identification of drug receptors from excitable membranes are performed by means of various physical and biochemical methods such as affinity chromatography, equilibrium dialysis, and nuclear magnetic resonance. These results are expected to provide us with solid and basic in formation for the reconstruction of excitable membranes in vitro and for the structure-activity relations for various drugs which, in turn, will give us a clue to improvements and creation of drugs of clinical importance.